Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function that frequently causes heart failure. Recent studies suggest that approximately 20% of dilated cardiomyopathies are familial and inherited as an X-linked or dominant trait. While some sporadic cases of dilated cardiomyopathy occur secondary to toxins, infection, or systemic illness, in many instances the etiology is unknown. This project proposes to use molecular genetic approaches to identify the chromosome(s) that encode genes which can be mutated to cause dilated cardiomyopathies that are transmitted in an autosomal dominant fashion (FDC). Using positional cloning we will identify both the causal genes and mutations that produce this condition. We will also assess the role of the FDC genes in causing nonfamilial heart failure. Identification of the genetic cause of dilated cardiomyopathy will enable preclinical diagnosis in families at risk and will eventually permit development of animal models for this condition that may improve therapeutic modalities. The goals of this project are highly integrated with those of other projects in this Heart Failure SCOR. Identification of the gene defect responsible for FDC will enable preclinical recognition of individuals at risk for heart failure and foster both longitudinal studies and preventive interventions. Further, identification of a genetic defect that causes FDC will foster basic studies to elucidate how myocyte structure and function are altered in response to mutated proteins and help to define compensatory responses. We believe that understanding the complex signals triggered by gene mutation should ultimately provide important insights into the molecular mechanisms for contractile dysfunction that cause heart failure.